Novel vitamin D analog for kidney cancer

用于肾癌的新型维生素 D 类似物

• 批准号: 7471169
• 负责人: RAHUL RAY
• 金额: $ 18.28万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471169
• 关键词: Accounting; Adult; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Calcitriol; Cancer cell line; Carcinoma; Catabolism; Cell Cycle; Cell Line; Cells; Cessation of life; Death Rate; Development; Disease; Dose; Epidemiologic Studies; Europe; Goals; Growth; Hormones; Human; Immunotherapy; Inhibition of Apoptosis; Intervention; Ligand Binding; Localized; Malignant Neoplasms; Malignant neoplasm of kidney; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Molecular; Mus; Neoplasms; Nephrectomy; Personal Satisfaction; Pilot Projects; Property; Prostatic Neoplasms; Public Health; RNA Interference; Radiation therapy; Rate; Regulation; Renal Cell Carcinoma; Renal carcinoma; Resistance; Role; Staging; Standards of Weights and Measures; Therapeutic; Toxic effect; United States; Vitamin D; Vitamin D Analog; Vitamin D3 Receptor; Xenograft Model; analog; bromoacetate; cancer cell; cell growth; crosslink; gene induction; kidney cell; mouse model; novel; prevent; raf Kinases; small molecule; success; tumor

DESCRIPTION (provided by applicant): Kidney cancer comprises approximately 3% of all adult malignancies, and account for over 30,000 cases and 12,000 deaths per year. Unfortunately, efficient intervention of this deadly disease is currently lacking, and effective therapy for this deadly disease is urgently needed. Numerous epidemiological studies have strongly demonstrated the importance of dietary vitamin D in preventing various cancers. In addition, therapeutic potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of vitamin D and its analogs in cancer is well-documented. However, inherent calcemic toxicity of this hormone, particularly at therapeutic doses, has prevented its general use as an anticancer agent, opening the door for the development of vitamin D analogs with potent antiproliferative activity with reduced systemic toxicity. Recently we developed a novel derivative of 1,25(OH)2D3 [11,25- dihydroxyvitamin D3-3-bromoacetate, 1,25(OH)2D3-3-BE] that covalently attaches 1,25(OH)2D3 inside the ligand-binding pocket of VDR. We demonstrated that 1,25(OH)2D3-3-BE strongly inhibits the growth of several human cancer cells, including a set of kidney cancer cells. We also demonstrated that 1,25(OH)2D3-3-BE reduces hormone-insensitive prostate tumor at 0.1-0.5 5g/kg dose level in a mouse xenograft model without significant toxicity. Collectively, these results demonstrate potential therapeutic utility of this compound in kidney cancer. The goal of this R21 proposal is to appraise the potential therapeutic value of 1,25(OH)2D3-3-BE in kidney cancer, and evaluate the molecular mechanism of this novel VDR-cross-linking derivative of 1,25(OH)2D3. These goals will be met by two specific aims: Specific Aim 1: Determine the efficacy of 1,25(OH)2D3-3-BE on human renal cell carcinoma in a mouse xenograft model; and Specific Aim 2: Evaluate the molecular mechanism of growth-inhibition and apoptosis by 1,25(OH)2D3-3-BE in kidney cancer cells. Successful completion of this pilot project will be crucial for the development of 1,25(OH)2D3-3-BE and similar VDR-alkylating analogs of vitamin D hormone for kidney cancer. PUBLIC HEALTH RELEVANCE: Inherent calcemic toxicity of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of vitamin D has prevented its general use as an anticancer agent. Recently we developed a novel derivative of 1,25(OH)2D3 that strongly inhibits the growth of several human kidney cancer cells, and induces programmed cell death in these cells. The goal of this project is to evaluate the therapeutic potential of this compound in kidney cancer.

描述（由申请人提供）：肾癌约占所有成人恶性肿瘤的3％，每年占30,000多例和12,000例死亡。不幸的是，目前缺乏对这种致命疾病的有效干预，迫切需要对这种致命疾病的有效疗法。许多流行病学研究强烈证明了饮食中维生素D在预防各种癌症中的重要性。此外，有充分的文献记录了1,25-二羟基维生素D3（1,25（OH）2d3），维生素D及其类似物的生物活性代谢产物的治疗潜力。然而，这种激素的固有钙化毒性，尤其是在治疗剂量下，已经阻止了其作为抗癌剂的普遍用途，为发展具有有效的抗增殖活性的维生素D类似物开辟了大门，具有降低的全身毒性。最近，我们开发了一种新颖的衍生物，以1,25（OH）2d3 [11,25-二羟基维生素D3-3-3-溴乙酸，1,25（OH）2d3-3-be]共同附着1,25（oh）2d3（oh）2d3。我们证明了1,25（OH）2d3-3-强烈抑制了几种人类癌细胞的生长，包括一组肾脏癌细胞。我们还证明了1,25（OH）2D3-3-BE在小鼠异种移植模型中以0.1-0.5 5g/kg剂量水平降低激素不敏感的前列腺肿瘤，而没有明显的毒性。总的来说，这些结果证明了这种化合物在肾癌中的潜在治疗效用。该R21提案的目的是评估肾癌中1,25（OH）2d3-3-be的潜在治疗价值，并评估这款新型VDR-Cross-link衍生物的分子机制为1,25（OH）2d3。这些目标将通过两个特定的目标来实现：具体目标1：确定小鼠异种移植模型中1,25（OH）2d3-3-be对人肾细胞癌的疗效；和特定目标2：评估肾癌细胞中1,25（OH）2d3-3-be的分子抑制和凋亡的分子机制。该试点项目的成功完成对于开发1,25（OH）2d3-3-be和类似的维生素D激素的VDR-Alkylating类似物至关重要。公共卫生相关性：1,25-二羟基维生素D3（1,25（OH）2D3）的固有钙化毒性，维生素D的生物活性代谢物已阻止其作为抗癌药的普遍用途。最近，我们开发了1,25（OH）2D3的新型衍生物，该衍生物强烈抑制了几个人类肾脏癌细胞的生长，并诱导这些细胞中编程的细胞死亡。该项目的目的是评估该化合物在肾癌中的治疗潜力。